Aripiprazole is a drug commonly known as an atypical antipsychotic agent. Using an aripiprazole aqueous suspension as an injectable formulation has been proposed for the administration of aripiprazole. In particular, a suspension obtained by suspending aripiprazole with a mean particle size of about 1 to about 10 μm in an aqueous vehicle is known to have excellent sustained-release properties and bioavailability (Patent Document 3).
In prior art, aseptic pulverization of bulk aripiprazole was difficult at the commercial production level. For example, a ball milling method, which uses ceramic beads widely used in wet milling, has problems: bead friction may cause contamination; additionally, ball mills capable of in-line sterilization are generally not commercially available currently.
Moreover, the ball mill pulverization method may possibly involve a problem of short-pass in which some large particles possibly slip through the beads. As shown in Patent Document 4, it is preferable to use bulk aripiprazole having a desired small particle size, preferably having a mean particle size of about 100 μm or less, more preferably about 95% of the crystals having a particle size less than 100 μm with a narrow particle size distribution. However, production of such bulk aripiprazole having a mean particle size of about 100 μm or less requires particular crystallization techniques like an impinging jet crystallization method, as described in Patent Document 4.
On the other hand, particle size reduction can be carried out using a high-pressure homogenizer; however, when a 10% suspension of aripiprazole having a mean particle size of more than 100 μm is pulverized with a high-pressure homogenizer, clogging occurs in the line, precluding pulverization. Therefore, it is desired to use aripiprazole preferably with a mean particle size of 100 μm or less.
However, suspending such aripiprazole with a mean particle size of about 100 μm or less in a vehicle solution is accompanied by foaming. Therefore, mixing under vacuum is necessary for the preparation of a homogeneous suspension (see Patent Document 3, Example 1 and paragraph 0089).
When mixing is carried out under vacuum, outside air may be introduced, which requires measures to prevent contamination from the external environment. Improvement in this aspect is desired.
Patent Document 1 discloses a method for preparing small particles containing a poorly water-soluble drug, comprising the steps of:
(a) mixing at high shear an admixture of a poorly water-soluble drug and one or more surface active substances in an aqueous carrier in the absence of an organic solvent within a first temperature range at or above the melting point of the poorly water-soluble drug to form a heated suspension containing the drug wherein the drug is molten;
(b) homogenizing the heated suspension in a first pressure range and within the first temperature range to form a heated homogenate containing the drug wherein the drug is molten;
(c) cooling the heated homogenate to a second temperature range below the melting temperature of the poorly water-soluble drug to form a transiently stable, cooled homogenate containing the drug;
(d) applying a particle stabilizing energetic process to the cooled homogenate within a second temperature range below the melting point of the drug and in a second pressure range to form a cooled dispersion of stabilized small particles containing the drug; and
(e) drying the cooled dispersion to form dried small particles containing the poorly water-soluble drug.
However, in the method of Patent Document 1, preparation of an emulsion heated at a temperature higher than the melting point of the drug is essential, and there is a problem in maintaining the crystal form.
Patent Document 2 discloses effective solubilization or dispersion means of poorly soluble compounds by adding a combination of a predetermined amount of an oily component (fat), an emulsifier, and cyclodextrin. It teaches that a homomixer is used for coarse emulsification, and that a high-pressure homogenizer or an ultrasonic homogenizer is used for fine emulsification. However, in Patent Document 2, the composition containing a poorly soluble compound that is solubilized or dispersed takes the form of a fat emulsion, and not an aqueous suspension.
Patent Document 3 discloses a method for preparing a sterile freeze-dried formulation comprising the steps of:
(a) preparing sterile bulk aripiprazole having a desired particle size distribution;
(b) preparing a sterile vehicle for the sterile bulk aripiprazole;
(c) combining the sterile aripiprazole and the sterile vehicle to form a sterile primary suspension that includes a sterile mixture of solids;
(d) reducing the mean particle size of the sterile mixture of solids in the sterile primary suspension, e.g., by an aseptic wet milling to within the range from about 1 to about 100 μm, particularly about 1 to 10 μm, to form a sterile final suspension; and
(e) freeze-drying the sterile final suspension to form the freeze-dried formulation.
It teaches that wet ball milling is preferred as the aseptic wet milling procedure in step (d).
Non-Patent Document 1 discloses that microfluidizers have two advantages over other methods of decreasing a mean particle size: the final products have no contaminants, and production is easily scaled up.    Patent Document 1: Japanese Unexamined Patent Publication No. 2003-531162    Patent Document 2: Japanese Unexamined Patent Publication No. 2005-22989    Patent Document 3: Japanese Unexamined Patent Publication No. 2007-509148    Patent Document 4: Japanese Unexamined Patent Publication No. 2007-509153    Patent Document 5: Japanese Patent No. 3760264    Patent Document 6: Japanese Patent No. 3750023    Non-Patent Document 1: Kathleen J. Illing, et al., “Use of Microfluidizer Processing for Preparation of Pharmaceutical Suspensions”, Pharm. Tech., October 1996, pages 78 to 88.    Non-Patent Document 2: “Study on Crystal Transformation of Aripiprazole” Satoshi Aoki, et al., The Fourth Japan-Korea Symposium on Separation Technology (Oct. 6-8, 1996), p. 937-940